Aspirin gained tremendous popularity during the 1918 Spanish Influenza virus pandemic,
50 years prior to the demonstration of their inhibitory action on prostaglandins.
Here, we show that during influenza A virus (IAV) infection, prostaglandin E2 (PGE2)
was upregulated, which led to the inhibition of type I interferon (IFN) production
and apoptosis in macrophages, thereby causing an increase in virus replication. This
inhibitory role of PGE2 was not limited to innate immunity, because both antigen presentation
and T cell mediated immunity were also suppressed. Targeted PGE2 suppression via genetic
ablation of microsomal prostaglandin E-synthase 1 (mPGES-1) or by the pharmacological
inhibition of PGE2 receptors EP2 and EP4 substantially improved survival against lethal
IAV infection whereas PGE2 administration reversed this phenotype. These data demonstrate
that the mPGES-1-PGE2 pathway is targeted by IAV to evade host type I IFN-dependent
antiviral immunity. We propose that specific inhibition of PGE2 signaling might serve
as a treatment for IAV.